Abstract: With the advent of the ""age of antibiotics"" in the 1940s, many believed that we had conquered these dangerous microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance had been sorely underestimated and today, infectious diseases are the second-leading cause of death worldwide and the third-leading cause of mortality in economically advanced countries. The ever-growing and significant problem of antibacterial resistance requires discovery of new leads. However, identification of the next generations of antibiotics will necessitate a change in the curent drug discovery paradigm. Pursuit of compounds that function through the commonly targeted mechanisms of action will not yield the combination of antibiotic potency and long-term efficacy necessary to combat resistant organisms. In fact, compounds that attack microbes through multiple, simultaneous mechanisms will be essential to anti-infective development. Public Health Relevance: This program will improve public health through the identification of the next generation of antimicrobial therapeutic agents, particularly focusing on more effective and long-lifetime treatments for drug resistant infections. To achieve this goal, we will develop and apply technologies for the discovery of drug leads from nature's vast reservoir of antibacterial natural products from plants and microorganisms.